Much evidence shows that the tricyclic
antidepressant, desipramine, apart front its
potent property of inhibiting the uptake of
noradrenaline (NA) (Iversen, 1975), also
exhibits an influence on central dopaminergic
systems. Desipramine enhances depletion of
dopamine (DA) in the striatum by a -methyl-m
-tyrosine, a finding that suggests an increase
in utilization of DA (Waldmeier, 1982), produces
significant elevation of the net efflux of
endogenous DA from the hypothalamus and striatum
(Myers and Tessel, 1984), inhibits the uptake of
DA into the corpus striatum (Randrup and
Braestrup, 1977; Koe, 1979). However,
concentrations of desipramine 100-1000-fold
greater are required to inhibit the uptake of DA
than of NA.
Enhancement of the release of DA and
inhibition of the uptake of DA by desipramine
can be expected to result in an increase in the
amount of DA in the synaptic cleft, which, in
turn, should affect behaviour that is dependent
on dopaminergic stimulation. Agents that
stimulate DA systems directly, such as
apomorphine or indirectly, such as
amphetamine, produce characteristic stereotyped
behaviour, hypermotility or induce sedation and
yawning behaviour in rats. The latter
effect, however, is induced by relatively small
doses of DA agonists (Mogilnicka
and Klimek, 1977; Dubuc, Protais, Colboc and
Costentin, 1982). Desipramine, even in large
doses, fails to provoke stereotypy but according
to biochemical findings, it does affect
dopaminergic systems. Therefore, in the prescrit
study it was decided to investigate the effect
on yawning. Additionally, the effect of some
other typical and atypical antidepressants on
yawning were tested. [...]
Discussion : The main finding of this
study was that desipramine and some other
antidepressants provoked yawning in rats. As
has been pointed out in the introduction,
yawning occurred in rats after administration of
relatively small doses of various DA agonists
that stimulate DA receptors either directly
(apomorphine) or indirectly (amphetamine,
nomifensine; Mogilnicka
and Klimek, 1977; Yamada and Furukawa,
1980). Reduction of the yawning induced by
desipramine by the DA-ergic blockers
(haloperidol, spiperone, pimozide) points to the
involvement of DA receptors in phenomenon
observed.
As desipramine is a potent inhibitor of the
uptake of NA, it can be expected that NA-ergic
stimulation plays a role in the induction of
yawning. This possibility, however, has to
be excluded because the NA-ergic antagonists,
prazosin and phenoxybenzamine, did not abolish
yawning induced by desipramine and, on the other
hand, another selective and potent inhibitor of
the uptake of NA, the active enantiomer of
(±)oxaprotiline - (+)oxaprotiline
(Waldmeier, Baumann, Hauser, Maître and
Storni, 1982) did not provoke yawning.
Furthermore, the prevention of yawning by
reserpine, as well as by a-MT, points to the
presence of neurotransmitters (DA, NA) being
necessary for the action of desipramine to
appear. It seems, therefore, in the light of
above finding that desipramine might induce
yawning by releasing DA from nerve endings. A
dopaminergic-cholinergic link bas been shown to
be involved in yawning (Yamada and Furukawa,
1980; Dubuc et al., 1982). Indeed, as was the
case with apomorphine-induced yawning,
scopolamine also blocked yawning provoked by
desipramine. However, cholinergic stimulation is
brought about indirectly, by DA-ergic activation
(which scems to be a primary effect), since
yawning induced by desipramine was blocked by DA
blockers. It must bc added that haloperidol did
not affect yawning induced by cholinomimetie
drug physostigrnine (Dubuc et al., 1982).
Among drugs that induce yawning to a lesser
extent than desipramine, are the tricyclics
imipramine and clomipramine, atypical
antidepressant trazodone and its metabolite
m-chlorophenylpiperazine, as well as
neuroleptics of the benzamine group sulpiride.
Imipramine induced yawning episodes of lesser
intensity, which suggests that it affects
DA-ergic systems to a smaller degree than does
desipramine. As imipramine is metabolized to
desipramine (Rickel and Weder, 1968; Daniel,
Adamus, Melzacka, Szymura and Vetulani, 1981),
its pharmacological effects can also be brought
about by its metabolite. Interestingly,
trazodone which blocks 5-HT receptors, as well
as m-chlorophenylpiperazine, which stimulates
them (Fuller and Snoddy, 1977, Maj, Palider and
Rawlôw, 1979) each provoked the occurrence
of yawning. It can, however, be argued that
yawning is due solely to stimulation of 5-HT
receptors as trazodone is metabolized to
m-chlorophenylpiperazine (Melzacka, Boksa and
Maj, 1979), a 5-HT agonist. However, lack of
inhibition of yawning induced by
m-chlorophenylpiperazine by the specific
5-HT-ergic blocker, metergoline excludes this
possibility. Therefore, it is not surprising
that no yawning episodes were observed after
administration of the strong and specific
inhibitor of the uptake of 5-HT citalopram
(Hyttel, 1982). The fact that haloperidol
prevented yawning induced by
m-chlorophenylpiperazine indicates a DA-ergic
action of m-chlorophenylpiperazine.
It is noteworthy that all the compounds which
induced yawning can influence the DA-ergic
system. As demonstrated with various methods,
clomipramine, trazodone and
m-chlorophenylpiperazine increase the turnover
of DA (Fuller and Snoddy, 1977; Waldmeier, 1982,
1984). Clomipramine, trazodone,
m-chlorophenylpiperazine and sulpiride increase
the turnover of DA in brain, probably by
blocking DA receptors (Fuller and Snoddy, 1977;
Keller, Burkard and Da Prada, 1980; Montanare,
Dall'Olio, Gandolfi and Vaccheri, 1982;
Waldmeier, 1982, 1984). The open question is how
to explain the presence of yawning if DA
receptors are blocked. Omitting at the moment
the speculation concerning the kind of DA
receptors responsible for yawning (pre- and
postsynaptic receptor mechanism?) it is assumed
that, in spite of the blockade of these
receptors, their stimulation is possible.
Following the speculation of Bunney (1984)
referring to the mechanism of action of
antipsychotic drugs, one can imagine that
receptor blockade is not very effective after
acute administration of antipsychotics or
neuroleptic-like drugs. A single dose of such a
drug would result, in an increase in release of
DA into the synaptic cleft, and due to the
consequential flooding of the cleft with DA
molecules and their competition with drug
molecules for the receptor, the DA receptors can
be stimulated. This mechanism could explam the
appearance of yawning after clomipramine
trazodone and sulpiride.
From the above findings it is concluded
that desipramine and some other antidepressant
drugs induce yawning behaviour and that a
DA-ergic mechanism is involved in this
behavioural manifestation.
